This study demonstrates degradation of synthetic wastewater in two MFCs hydraulically connected in series. To maximize chemical oxygen demand (COD) removal, external resistance of each MFC is optimized using a perturbation–observation maximum power point algorithm. Under optimal operating conditions a removal efficiency over 90% is achieved at an influent acetate concentration of 750 mg L–1 and organic loading rates ranging from 0.75 to 3.0 g L–1 day–1. Furthermore, regression analysis is used to correlate current and power output of each MFC with the analytically measured COD concentrations, thus providing a means for online COD estimations. The accuracy of online COD estimations is further improved by developing a model-based soft-sensor.